Individuals with an underlying HIV-infection have an increased risk of developing AIDS-defining and non-AIDS defining cancer. This is a significant healthcare and economical concern as the HIV-infected population is surviving longer and living fuller and productive lives owing to the advent of antiretroviral therapy (ART). Several parameters are associated with this increased incidence in cancer, but two factors that are consistent with cancer development in general are the increasing age of individuals and HIV infection, which suggests there is interplay between aging and HIV infection that leads to an increased incidence of cancer development and progression. Aging is well known to be a risk factor for developing non-AIDS-defining cancer, however; aged HIV-infected individuals are 3 times more likely to develop non-AIDS-defining cancer than the comparable normal immunocompetent aged population. Thus, viral, cellular and molecular factors that change over time due to aging and HIV-infection must intersect to accelerate the processes that make this population more at risk to develop cancer. Aspects of this can be studied longitudinally in HIV-infected individuals, but this approach has shortcomings and is dependent upon the enrollment of patients, who may drop out due to relocation or disinterest. An alternative approach is to investigate an animal model that recapitulates most, if not all, aspects of HIV pathogenesis. Here, we propose to use the widely accepted simian immunodeficiency virus (SIV) infected nonhuman primate (NHP) model that recapitulates multiple aspects of HIV pathogenesis, including development of AIDS-related malignancies. This outbred model approximates HIV infection and can be surgically and immunologically manipulated to investigate the alterations that occur and lead to cancer development and progression. Our studies will be performed through a series of experimental in vivo infections and characterization of the host immune response and next generation sequencing of biological samples, including cancer tissues. Combining these types of in vitro and in vivo experiments to address cancer development and progression will enable researchers to dissect how alterations in the host impact disease in susceptible populations and how scientists can shift the pendulum in favor of the host.